ABSTRACT Despite decades of research, an ideal non-thrombogenic and antibacterial surface has yet to be identified to eliminate the need for systemic anticoagulation and risks of infection. Blood-material interactions are critical to the success of implantable medical devices including simple catheters, stents and grafts, insulation materials for electrical leads of pacemakers and defibrillators, and complex extracorporeal artificial organs, which are used in thousands of patients every day. The major limiting factors to clinical applications of blood-contacting materials are 1) platelet activation and thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Commercial heparin-coated catheters have been shown to preserve fibrinogen levels, but it does not prevent the alternate hemostatic pathway of platelet activation and adhesion. Surface-induced thrombosis remains a significant challenge for such devices and systemic anticoagulation is required to prevent clotting but also results in a major risk of hemorrhage. In addition, catheters coated with antiseptics or antibiotics decrease the risk of bacterial infection, but do not prevent biofilm formation that shields bacteria from antibiotics. Therefore, there is a necessity and opportunity to combine strategies for preventing thrombosis and infection into single implantable device coatings for enhanced patency and safety. Recent work over the past 5 years has demonstrated that nitric oxide (NO) release from polymer surfaces can prevent platelet activation and bacterial infection. This technology is based on the fact that NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. Further, NO released within the sinus cavities, and by neutrophils and macrophages, functions as a potent natural antimicrobial and antiviral agent. Recently we discovered that all of the positive effects of NO release can be achieved from polymers doped with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release alone can inhibit platelet function locally at the polymer/blood interface, but it does not prevent fibrinogen adsorption and fibrin formation, which plays a key role in a clot formation. In contrast, zwitterionic materials have been demonstrated to resist protein adsorption down to < 0.3 ng/cm2, where a monolayer of protein coverage on a surface can be as high as 100?500 ng/cm2. Zwitterionic materials have a stronger hydration ability compared with existing hydrophilic polymers; this accounts for their ultra-low fouling property. The goal of this proposal is to develop, optimize, and evaluate novel intravascular catheters that will combine agents that inhibit bacteria growth, platelet adhesion, and activation via NO release as well as inhibit biofouling (bacteria and fibrinogen adhesion) using immobilized zwitterionic top-coat. The new coatings will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined effect of NO-releasing polymer and zwitterion in long-term (up to 30 d) intravascular catheter-type devices on clotting and infection. Due to high commercialization potential, leading biomedical companies including Cook Medical and MC3 have been interest in our technology.